1. Field of the Invention
High levels of gastrin production are associated with autocrine pancreatic tumors. Gastrin levels and growth of human pancreatic cancer can be down-regulated by employing miRNA.
2. Description of Related Art
The gastrointestinal peptide gastrin is involved in growth of the gastrointestinal tract1,2. In addition, gastrin has been shown to play a role in proliferation of several neoplasms, including colon cancer3-6, gastric cancer7,8, lung cancer9, and pancreatic cancer10-12. Gastrin immunoreactivity is found in the fetal pancreas, but its expression is limited to the G-cells of the stomach in the adult13. Examination of cultured human pancreatic cancer cell lines has shown that gastrin is reexpressed in these cells and stimulates their growth by an autocrine mechanism14. Short-term administration of gastrin antisense oligonucleotides decreased cancer cell proliferation, further substantiating the endogenous role of gastrin on growth14,15. Selective radioimmunoassay further demonstrated that the form of gastrin produced endogenously in pancreatic cancer cells and tissues was consistent with the fully processed form, gastrin-1716. The fact that gastrin is produced by human pancreatic cancer cells suggests also a role for this peptide in development of pancreatic cancer. Knockdown of gastrin gene expression with an antisense gastrin cDNA decreases growth of human BxPC-3 pancreatic cancer xenografts grown subcutaneously in nude mice17.
The mechanism by which gastrin exerts its trophic effects continues to be investigated. Gastrin, in various forms including fully processed and amidated gastrin, progastrin, or glycine-extended gastrin, has been shown to induce proliferation in several types of cancers18. The effect of gastrin is mediated through increased transcription of ligands of the EGF receptor (EGFR)19,20, the REG protein21, and cyclooxygenase-222. Gastrin promotes growth and survival of rat AR4-2J pancreatic cancer cells by activating small GTP-binding proteins (Ras, Rac, Rho, and Cdc42), while the gastrin gene promoter is synergistically activated by the TGFβ/SMAD and Wnt signaling pathways23,24. Tomkova and colleagues have shown that the transcription factor p73, a homolog of the p53 tumor suppressor gene, binds to the gastrin gene promoter in human gastric cancer cells and increases transcription of gastrin mRNA25. In addition, gastrin has an anti-apoptotic effect through stimulation of PKB/Akt signaling and activation of NF-κB26, and enhances angiogenesis via modulation of heparin-binding epidermal-like growth factor27.
Gastrin has recently been a target for the development of anti-cancer therapeutics. Brett and coworkers28 tested the efficacy of an anti-gastrin immunogen, G17DT, in pancreatic cancer patients and reported increased survival, however this occurred only in a sub-group of subjects that developed anti-gastrin antibodies. Gastrazole, a gastrin receptor antagonist, was given to advanced pancreatic cancer patients with an improvement in overall patient survival that was comparable to standard treatment of 5-FU29. When combined with gemcitabine, a newer orally active gastrin receptor antagonist (Z-360) has shown modest efficacy against orthotopic pancreatic tumors in mice30. Transient knockdown of gastrin gene expression by transfecting pancreatic cancer cells with antisense gastrin constructs31 or with gastrin siRNA32 decreased gastrin levels and tumor cell proliferation in vitro.